‘Lactic acid bacterium’ is a general term for bacteria that decompose sugar to produce lactic acid, thus generating energy, and includes Lactobacillus genus bacteria, Bifidobacterium genus bacteria, Lactococcus genus bacteria, Streptococcus genus bacteria, and Enterococcus genus bacteria.
Bacteria can be roughly divided, in terms of oxygen demand for their growth, into aerobes, which require oxygen for growth, and anaerobes, which do not require oxygen. Furthermore, the anaerobes can be divided into obligatory anaerobes, which cannot grow in the presence of oxygen, and facultative anaerobes, which can grow in either the presence or absence of oxygen.
Among the lactic acid bacteria above, Bifidobacterium genus bacteria are obligatory anaerobes, and Lactobacillus genus bacteria, Lactococcus genus bacteria, Streptococcus genus bacteria, Enterococcus genus bacteria, etc. are facultative anaerobes.
Lactic acid bacteria are conventionally commonly used in the food field, and recently their effect as probiotics of promote health maintenance of a host by improving the balance of enterobacterial flora has been noted.
Furthermore, there have been a number of reports relating to their applications in the medicinal field, and with regard to the treatment of a tumor, in addition to direct application as an antitumor drug, applications as an immunostimulant, an IgE production inhibitor, a humoral immunity recovery agent, an interleukin 12 production promoter, etc. have been reported.
For example, it has been reported that a composition comprising one or more selected from Lactobacillus genus bacteria, Bifidobacterium genus bacteria, Pediococcus genus bacteria, Streptococcus genus bacteria, and Leuconostoc genus bacteria exhibits an immunostimulatory action (antitumor activity) (ref. e.g. Patent Publication 1).
In addition, various types of useful lactic acid bacteria have been reported as a therapeutic agents for tumor such as an antitumor drug, an IgE production inhibitor, a humoral immunity recovery agent, an interleukin 12 production promoter, an immunostimulant (ref. e.g. Patent Publications 2 to 7).
Furthermore, with regard to Lactobacillus genus bacteria in particular, there have been reported Lactobacillus genus bacteria that are useful as tumor growth inhibitors or malignant tumor recurrence inhibitors (ref. e.g. Patent Publications 8 to 11).
However, as described above, among these lactic acid bacteria, all other than the Bifidobacterium genus bacteria are facultative anaerobes, which grow in an environment having a relatively high oxygen concentration. Therefore, naturally these bacteria is highly likely to accumulate and grow in normal tissue as well as in tumor tissue that is in an anaerobic environment, and the occurrence of side effects in the normal tissue is concerned.
On the other hand, with regard to Bifidobacterium genus bacteria, which are obligatory anaerobes, methods for using them in the treatment of a disease that is in an anaerobic environment such as a solid tumor have been proposed.
For example, Bifidobacterium longum, which is a Bifidobacterium genus bacterium, has been confirmed that, upon systemic intravenous administration, it quickly disappears from normal tissue and specifically accumulates and grows in the solid tumor region, and its application to the treatment of a solid tumor is anticipated (ref. e.g. Non-patent Publications 1 and 2).
Further, Bifidobacterium longum was transformed to express cytosine deaminase (hereinafter, called CD) as a target active protein, which is an enzyme that converts 5-fluorocytosine (hereinafter, called 5-FC), which is a prodrug (precursor) of 5-fluorouracil (hereinafter, called 5-FU) with antitumor activity, into 5-FU, and has been confirmed that, upon being intravenously administrated, the bacteria specifically accumulate and grow in the tumor site and express the target protein, and it has been reported that the bacterium is very promising as a safe therapeutic agent for solid tumor having no possibility of inducing side effects in normal tissue (ref. e.g. Patent Publication 12 and Non-patent Publications 3 and 4).